Public Health Relevance Statement The goal of this project is to develop new therapies for Type 1 diabetes that do not substantially compromise the ability of the immune system to protect against invasive pathogens. Project Abstract As Type 1 diabetes is caused by autoimmune destruction of insulin-producing [unreadable]-islet cells, modulation of the ongoing autoimmune response in recently diagnosed patients may inhibit progression of the disease. A significant obstacle, however, is that current strategies of immunosuppression for treatment of autoimmune diseases often increase patient susceptibility to infections. We hypothesize that the immunoregulatory responses induced by chronic helminth infections can suppress the inappropriate inflammation of autoimmune disorders without significantly impairing the ability of the immune response to fight invasive pathogens. While patients with chronic helminth infections are not clinically immunocompromised, both human and animal studies demonstrate that chronic parasitic worm infections are protective against autoimmune diseases. Recently, our laboratory has demonstrated that infection of non-obese diabetic (NOD) mice with Litomosoides sigmodontis, a tissue-invasive parasitic filarial worm of rodents, protects against the development of diabetes. We have also shown that this helminth-mediated protection is associated with an increase in natural T- regulatory cells. Live infection is not required for protection, as injection of a crude homogenate of L. sigmodontis antigens also protects against diabetes. The major objectives for this proposal are to determine the mechanisms by which L. sigmodontis protects against the development of Type 1 diabetes in NOD mice and to identify the specific molecules of L. sigmodontis that can induce this protection. We also plan to determine the potential therapeutic utility L. sigmodontis-derived therapies may have. Specifically, we plan to assess the degree to which L. sigmodontis infection and antigen administration can reverse established disease and the impact these interventions have on the immune system's ability to protect against invasive pathogens.